Crossveinless-c, the Drosophila homolog of tumor suppressor DLC1, regulates directional elongation of dendritic branches via down-regulating Rho1 activity

Laboratory of Cell Recognition and Pattern Formation, Graduate School of Biostudies, South Campus Research Building (Building G), Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Genes to Cells (Impact Factor: 2.81). 04/2010; 15(5):485-500. DOI: 10.1111/j.1365-2443.2010.01399.x
Source: PubMed


Diverse neuronal subtypes develop distinctive morphologies of dendritic arbors that receive synaptic or sensory inputs. Dendritic arbors of many subtypes take on a polarized shape, and one underlying mechanism is unidirectionally biased elongation of dendritic branches. As reported herein, we found that Drosophila Crossveinless-c (Cv-c) was a key regulator for such directional growth. In the cv-c mutant, two subclass of multidendritic sensory neurons examined formed dorsally directed branches; however, dendritic branches had difficulty in growing along the anterior-posterior (A-P) body axis. Cv-c belongs to the family of Rho GTPase-activating proteins (RhoGAPs) and is the homolog of human tumor suppressor DLC1. The RhoGAP activity of Cv-c was required cell-autonomously for the A-P-oriented growth, and Cv-c elevated the GTPase activity of Rho1 and Cdc42 in a cell-free assay. Our analysis of genetic interactions suggested that Rho1 was the target of Cv-c in vivo. All of our results suggest that Cv-c contributes to sprouting and subsequent growth of the A-P-oriented branches through negative regulation of Rho1. We discuss a role of Cv-c in dendritic growth in response to environmental cues.

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    • "To visualize dendrites and /or express transgenes, we used the following Gal4 drivers: Gr28b.c5152 and Gal45-4053. To express fluorescent proteins, we used UAS-mCD8:GFP (#5137 of the Bloomington Stock Center) or UAS-Venus-pm445455. Other strains used were dinr33956, Aktq57, TorΔP58, rok259, UAS-dicer2 (#60009 of Vienna Drosophila RNAi Center), UAS-raptorRNAi (HMS00124/#34814 of the Bloomington Stock Center), UAS-mCherryRNAi (#35785 of the Bloomington Stock Center), UAS-CHORDRNAi (this study), UAS-Dp110[D954A] (#25918 of the Bloomington Stock Center), UAS-rokRNAi (GD1522/#3793 and KK107802/#104675 of the Vienna Drosophila RNAi Center; JF03225/#28797, HMS01311/#34324, and GL00209/#35305 of the Bloomington Stock Center), UAS-hsp90RNAi (HMS00899/#33947 of the Bloomington Stock Center) and UAS-Rok.CAT48.2 "
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    ABSTRACT: Most organs scale proportionally with body size through regulation of individual cell size and/or cell number. Here we addressed how postmitotic and morphologically complex cells such as neurons scale with the body size by using the dendritic arbor of one Drosophila sensory neuron as an assay system. In small adults eclosed under a limited-nutrition condition, the wild-type neuron preserved the branching complexity of the arbor, but scaled down the entire arbor, making a "miniature". In contrast, mutant neurons for the Insulin/IGF signaling (IIS) or TORC1 pathway exhibited "undergrowth", which was characterized by decreases in both the branching complexity and the arbor size, despite a normal diet. These contrasting phenotypes hinted that a novel regulatory mechanism contributes to the dendritic scaling in wild-type neurons. Indeed, we isolated a mutation in the gene CHORD/morgana that uncoupled the neuron size and the body size: CHORD mutant neurons generated miniature dendritic arbors regardless of the body size. CHORD encodes an evolutionarily conserved co-chaperone of HSP90. Our results support the notion that dendritic growth and branching are controlled by partly separate mechanisms. The IIS/TORC1 pathways control both growth and branching to avert underdevelopment, whereas CHORD together with TORC2 realizes proportional scaling of the entire arbor.
    Scientific Reports 03/2014; 4:4415. DOI:10.1038/srep04415 · 5.58 Impact Factor
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    • "For example, in vertebrates, studies have demonstrated that Rho GTPases are activated by sensory stimuli and that activity-dependent dendritic growth requires activation of Rac1 and Cdc42, and decreased RhoA activation [14], [15]. In Drosophila, RhoA/Rho1 has been implicated in restricting dendritic outgrowth in both mushroom body neurons [16] and in da neurons where is it negatively regulated by the RhoGAP Crossveinless-c [17]. In contrast, Rac1 has been demonstrated to promote dendritic branching complexity in da neurons [18]–[21] as well as LPTC neurons in the CNS where it modulates the number of dendritic spines [22]. "
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    ABSTRACT: As the primary sites of synaptic or sensory input in the nervous system, dendrites play an essential role in processing neuronal and sensory information. Moreover, the specification of class specific dendrite arborization is critically important in establishing neural connectivity and the formation of functional networks. Cytoskeletal modulation provides a key mechanism for establishing, as well as reorganizing, dendritic morphology among distinct neuronal subtypes. While previous studies have established differential roles for the small GTPases Rac and Rho in mediating dendrite morphogenesis, little is known regarding the direct regulators of these genes in mediating distinct dendritic architectures. Here we demonstrate that the RhoGEF Trio is required for the specification of class specific dendritic morphology in dendritic arborization (da) sensory neurons of the Drosophila peripheral nervous system (PNS). Trio is expressed in all da neuron subclasses and loss-of-function analyses indicate that Trio functions cell-autonomously in promoting dendritic branching, field coverage, and refining dendritic outgrowth in various da neuron subtypes. Moreover, overexpression studies demonstrate that Trio acts to promote higher order dendritic branching, including the formation of dendritic filopodia, through Trio GEF1-dependent interactions with Rac1, whereas Trio GEF-2-dependent interactions with Rho1 serve to restrict dendritic extension and higher order branching in da neurons. Finally, we show that de novo dendritic branching, induced by the homeodomain transcription factor Cut, requires Trio activity suggesting these molecules may act in a pathway to mediate dendrite morphogenesis. Collectively, our analyses implicate Trio as an important regulator of class specific da neuron dendrite morphogenesis via interactions with Rac1 and Rho1 and indicate that Trio is required as downstream effector in Cut-mediated regulation of dendrite branching and filopodia formation.
    PLoS ONE 03/2012; 7(3):e33634. DOI:10.1371/journal.pone.0033634 · 3.23 Impact Factor
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    ABSTRACT: Analysis of early steps in muscular system development of invertebrates and vertebrates shows that early steps of myogenesis are regulated by genes-orthologs mainly belonging to two families, Pax and bHLH. In the majority of the following organisms, muscles formation (steps of determination and the earliest steps of myogenesis) is regulated by genes orthologs Pax3 which belong to the family Pax: nematodes (Caenorhabditis elegans, Pristionchus pacificus), insects (Drosophila melanogaster), echinoderms (Strongylocentrotus purpuratus), sea squirts (Ciona intestinalis, Holocynthia roretzi), fishes (Danio rerio), amphibians (Xenopus laevis), birds, and mammals (mouse, rat). The nematode C. elegans is an exception since formation of its muscles in this period is regulated by homeobox gene Pal-1 belonging to the family Caudal. The sea squirt C. intestinalis is also an exception because the earliest steps of development involved in further muscle formation are accompanied by activation of the gene CiSna (snail) (gene family basic Zinc finger). The next steps of myogenesis in all analyzed species are regulated by genes orthologs belonging to the family of transcriptional factors bHLH. They along with genes Pax3 are characterized by a high extent of homology in all studied groups of animals.
    Biology Bulletin 07/2012; 39(4). DOI:10.1134/S1062359012040085 · 0.25 Impact Factor
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